Neuronal degeneration and death occur during development, during senescence, and as a consequence of pathological events throughout life. Neuronal survival and function are critically influenced by the actions of neurotrophic factors. We are investigating the physiologic roles of the recently identified neurotrophic factors GDNF, Artemin, Neurturin and Persephin. Together, they represent a family of proteins that are a distantly related subgroup (GDNF Family Ligands or GFLs) of the TGFbeta superfamily. GFLs utilizes a receptor complex composed of a signaling component (the Ret tyrosine kinase), and a binding component (a member of a family of recently identified GPI-linked co-receptors (GFRalpha family). Experiments using in vitro cultures have shown that GF ligands support the survival of a variety of CNS (dopaminergic midbrain, spinal cord motor) and PNS neurons (sensory, sympathetic, parasympathetic, enteric). In this proposal, we outline experiments aimed at determining the molecular interactions between GF ligands and the GFRalpha/Ret receptor complexes. The physiologic roles of these ligands and cognate GFRalpha coreceptors will be investigated by studying mice that lack one or more of these components. Through this type of analysis, neuronal populations dependent on these factors for survival as well as maintenance and function will be identified. Further analysis will examine the role of these factors in Schwann cell biology and in regulating Schwann cell-neuronal interactions during development and nerve regeneration. From these studies further understanding concerning the role of GFLs in disease processes, as well as insights into modulating GFL signaling, will become available. This is vital information because these neurotrophic factors influence neurons involved in several neurodegenerative diseases (Parkinson's and ALS), neurons affected in peripheral neuropathies of chronic diseases such as diabetes, and enteric neurons which function poorly in gut motility syndromes that accompany chronic diseases. Since both chronic as well as acute nervous system injuries are characterized by structural damage, disease-induced apoptosis, and neuronal dysfunction, neurotrophic factors, such as the GF ligands, have potential value as therapeutic agents for these conditions.